Trial Outcomes & Findings for Efficacy and Safety of Imipenem+Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium+Imipenem+Cilastatin in Imipenem-Resistant Bacterial Infection (MK-7655A-013) (NCT NCT02452047)

NCT ID: NCT02452047

Last Updated: 2018-10-19

Results Overview

The percentage of participants with FOR was determined for Groups 1 and 2. FOR was determined based on clinically relevant outcomes for the primary site of infection as follows: HABP/VABP: survival through Day 28; cIAI: favorable clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required, and no unplanned surgical or percutaneous drainage procedures) at Day 28; cUTI: favorable composite clinical response (all pretherapy symptoms of index infection resolved with no evidence of resurgence, no additional antibiotic therapy required) and microbiological response (urine culture shows sustained eradication of the baseline uropathogen \[e.g., ≥10\^5 CFU/mL at study entry is reduced to \<10\^4 CFU/mL\]) at Early Follow-up (EFU).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

50 participants

Primary outcome timeframe

Up to Day 30 (up to 9 days after completing study treatment)

Results posted on

2018-10-19

Participant Flow

Adult participants with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), complicated intra-abdominal infection (cIAI), or complicated urinary tract infection (cUTI) were recruited at 35 study centers in 17 countries.

Participant milestones

Participant milestones
Measure	Group 1: Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Overall Study STARTED	31	16	3
Overall Study COMPLETED	27	11	1
Overall Study NOT COMPLETED	4	5	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Group 1: Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Overall Study Adverse Event	0	1	1
Overall Study Death	1	3	1
Overall Study Physician Decision	1	0	0
Overall Study Lost to Follow-up	1	1	0
Overall Study Withdrawal by Subject	1	0	0

Baseline Characteristics

Efficacy and Safety of Imipenem+Cilastatin/Relebactam (MK-7655A) Versus Colistimethate Sodium+Imipenem+Cilastatin in Imipenem-Resistant Bacterial Infection (MK-7655A-013)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n=3 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Total n=50 Participants Total of all reporting groups
Age, Continuous	56.1 Years STANDARD_DEVIATION 16.5 • n=5 Participants	62.8 Years STANDARD_DEVIATION 14.9 • n=7 Participants	50.0 Years STANDARD_DEVIATION 23.1 • n=5 Participants	57.9 Years STANDARD_DEVIATION 16.4 • n=4 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	6 Participants n=7 Participants	2 Participants n=5 Participants	19 Participants n=4 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	10 Participants n=7 Participants	1 Participants n=5 Participants	31 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) White	26 Participants n=5 Participants	15 Participants n=7 Participants	3 Participants n=5 Participants	44 Participants n=4 Participants
Race (NIH/OMB) More than one race	4 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	4 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Up to Day 30 (up to 9 days after completing study treatment)

Population: Participants in Groups 1 and 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=21 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=10 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With Favorable Overall Response (FOR)	71.4 Percentage of Participants Interval 49.8 to 86.4	70.0 Percentage of Participants Interval 39.2 to 89.7	—

PRIMARY outcome

Timeframe: Up to Day 35 (up to 14 days after completing study treatment)

Population: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 AEs during treatment and 14-day follow-up was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n=3 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With ≥1 Adverse Events (AEs)	71.0 Percentage of Participants	81.3 Percentage of Participants	100.0 Percentage of Participants

PRIMARY outcome

Timeframe: Up to Day 35 (up to 14 days after completing study treatment)

Population: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 SAEs during treatment and 14-day follow-up was determined. An SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n=3 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With ≥1 Serious Adverse Events (SAEs)	9.7 Percentage of Participants	31.3 Percentage of Participants	100.0 Percentage of Participants

PRIMARY outcome

Timeframe: Up to Day 35 (up to 14 days after completing study treatment)

Population: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related AEs during treatment and 14-day follow-up was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n=3 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With ≥1 Drug-Related AEs	16.1 Percentage of Participants	31.3 Percentage of Participants	33.3 Percentage of Participants

PRIMARY outcome

Timeframe: Up to Day 35 (up to 14 days after completing study treatment)

Population: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

The percentage of participants in Groups 1, 2, and 3 experiencing ≥1 drug-related SAEs during treatment and 14-day follow-up was determined. A drug-related SAE is any untoward medical occurrence that, at any dose, results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant injury/incapacity; is a congenital anomaly/birth defect; or is an other important medical event, that is considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n=3 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With ≥1 Drug-Related SAEs	0.0 Percentage of Participants	0.0 Percentage of Participants	33.3 Percentage of Participants

PRIMARY outcome

Timeframe: Up to Day 21

Population: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

The percentage of participants in Group 1, 2, and 3 discontinuing from study drug due to ≥1 AEs during the treatment period was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n=3 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants Discontinuing From Study Therapy Due to ≥1 AEs	0.0 Percentage of Participants	18.8 Percentage of Participants	33.3 Percentage of Participants

PRIMARY outcome

Timeframe: Up to Day 21

Population: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

The percentage of participants in Groups 1, 2, and 3 discontinuing from study drug due to ≥1 drug-related AEs during the treatment period was determined. A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered by the investigator to be related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n=3 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants Discontinuing From Study Therapy Due to ≥1 Drug-Related AEs	0.0 Percentage of Participants	12.5 Percentage of Participants	33.3 Percentage of Participants

PRIMARY outcome

Timeframe: Up to Day 35 (up to 14 days after completing study treatment)

Population: All participants in Groups 1 and 2 who received ≥1 dose of study drug are included. Group 3 data is not shown for this measure because there are only 3 participants.

The percentage of participants experiencing AEs that occurred in ≥4 participants within either Group 1 or Group 2 was assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Statistical analysis included only Groups 1 and 2 as indicated by the protocol; Group 3 had \<4 participants and therefore no data are presented.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group Pyrexia	12.9 Percentage of Participants	12.5 Percentage of Participants	—
Analysis of Specific AEs With an Incidence of ≥4 Participants in a Treatment Group Blood creatinine increased	0.0 Percentage of Participants	25.0 Percentage of Participants	—

PRIMARY outcome

Timeframe: Up to Day 35 (up to 14 days after completing study treatment)

Population: All participants in Groups 1, 2, and 3 who received ≥1 dose of study drug are included.

The percentage of participants in Groups 1, 2, and 3 having ECIs within 2 categories was determined. Category 1 ECIs included post-baseline laboratory values of an elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value that is ≥3x upper limit of normal (ULN) and an elevated total bilirubin value that is ≥2x ULN and (at the same time) an alkaline phosphatase value that is ≤2x ULN. Category 2 ECIs included a confirmed elevated AST or ALT value that is ≥5x ULN. Statistical analysis included only Groups 1 and 2 as indicated by the protocol.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam n=3 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With ≥1 Events of Clinical Interest (ECI) Category 1 ECI	0.0 Percentage of Participants	12.5 Percentage of Participants	—
Percentage of Participants With ≥1 Events of Clinical Interest (ECI) Category 2 ECI	0.0 Percentage of Participants	12.5 Percentage of Participants	—

SECONDARY outcome

Timeframe: Up to Day 35 (up to 14 days after completing study treatment)

Population: All participants in Groups 1 and 2 who received ≥1 dose of study drug are included. Per protocol, Group 3 was not included in the nephrotoxicity analysis.

Treatment-emergent nephrotoxity was assessed in Groups 1 and 2 as indicated by the protocol (Group 3 was not included). Nephrotoxicity for participants with normal baseline serum creatinine levels (\<1.2 mg/dL) was defined as "doubling of serum creatinine to \>1.2 mg/dL or reduction in creatinine clearance (ClCR) of ≥50%". Nephrotoxicity for participants with pre-existing renal dysfunction (baseline serum creatinine level ≥1.2 mg/dL) was defined as "increase in serum creatinine by ≥1 mg/dL or reduction from baseline ClCR of ≥20% or need for renal replacement therapy (RRT)".

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=31 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=16 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With ≥1 Events of Treatment-Emergent Nephrotoxicity	10.3 Percentage of Participants Interval 2.8 to 27.2	56.3 Percentage of Participants Interval 33.2 to 76.9	—

SECONDARY outcome

Timeframe: Day 28

The percentage of participants with FCR at Day 28 was determined for Groups 1 and 2. FCR at Day 28 was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=21 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=10 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With Favorable Clinical Response (FCR) at Day 28	71.4 Percentage of Participants Interval 49.8 to 86.4	40.0 Percentage of Participants Interval 16.7 to 68.8	—

SECONDARY outcome

Timeframe: Up to Day 28

Population: Participants in Group 1 and Group 2 who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

The percentage of participants with all-cause mortality up to Day 28 was determined for Groups 1 and 2.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=21 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=10 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With All-cause Mortality Up to Day 28	9.5 Percentage of Participants Interval 1.4 to 30.1	30.0 Percentage of Participants Interval 10.3 to 60.8	—

SECONDARY outcome

Timeframe: OTX (Day 3)

The percentage of participants with a FCR at OTX was determined for Groups 1 and 2. FCR at OTX was defined as "improved". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=21 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=10 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With FCR on Therapy (OTX)	81.0 Percentage of Participants Interval 59.4 to 92.9	40.0 Percentage of Participants Interval 16.7 to 68.8	—

SECONDARY outcome

Timeframe: At EOT (up to Day 21)

The percentage of participants with FCR at EOT was determined for Groups 1 and 2. FCR at EOT was defined as "cure" or "improved". Cure was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed". Improved was defined as "all or most pretherapy signs and symptoms of index infection have improved or resolved, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed.

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=21 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=10 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With FCR at End of Therapy (EOT)	90.5 Percentage of Participants Interval 69.9 to 98.6	60.0 Percentage of Participants Interval 31.2 to 83.3	—

SECONDARY outcome

Timeframe: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])

The percentage of participants with FCR at EFU was determined for Groups 1 and 2. FCR at EFU was defined as "sustained cure" or "cure". Sustained cure (for participants with "cure" response at the prior visit) was defined as "all pretherapy signs and symptoms of index infection resolved with no evidence of resurgence and no additional antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures have been performed". Cure (for participants with "improved" response at EOT visit) was defined as "all pretherapy signs and symptoms of index infection resolved or returned to preinfection status, and no additional IV antibiotic therapy required, and (for cIAI participants) no unplanned surgical procedures or percutaneous drainage procedures performed".

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=21 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=10 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of Participants With FCR at EFU	81.0 Percentage of Participants Interval 59.4 to 92.9	50.0 Percentage of Participants Interval 23.7 to 76.3	—

SECONDARY outcome

Timeframe: OTX (Day 3)

Population: Participants in Group 1 and Group 2 with cUTI who received ≥1 dose of each trial drug within a given IV treatment regimen, and who had a baseline bacterial pathogen that met inclusion criteria, are included. As per protocol, efficacy data from open-label Group 3 was considered exploratory and not included in the comparative analysis.

The percentage of participants with FMR at OTX was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at OTX showing eradication (i.e., ≥10\^5 colony forming units \[CFU\]/mL at baseline was reduced to \<10\^4 CFU/mL at OTX) of the uropathogen".

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=11 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=5 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of cUTI Participants With Favorable Microbiological Response (FMR) at OTX	100.0 Percentage of Participants Interval 70.0 to 100.0	100.0 Percentage of Participants Interval 51.1 to 100.0	—

SECONDARY outcome

Timeframe: At EOT (up to Day 21)

The percentage of participants with FMR at EOT was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EOT showing eradication (i.e., ≥10\^5 CFU/mL at baseline was reduced to \<10\^4 CFU/mL at EOT) or sustained eradication (i.e., ≥10\^5 CFU/mL at baseline that was reduced to \<10\^4 CFU/mL previously remained \<10\^4 CFU/mL at EOT) of the uropathogen".

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=11 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=5 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of cUTI Participants With FMR at EOT	100.0 Percentage of Participants Interval 70.0 to 100.0	100.0 Percentage of Participants Interval 51.1 to 100.0	—

SECONDARY outcome

Timeframe: EFU (Between Day 10 and Day 30 [5 to 9 Days after EOT])

The percentage of participants with FMR at EFU was determined for participants with cUTI in Groups 1 and 2. FMR was defined as "urine culture results at EFU showing sustained eradication (i.e., ≥10\^5 CFU/mL at baseline that was reduced to \<10\^4 CFU/mL previously remained \<10\^4 CFU/mL at EFU) of the uropathogen".

Outcome measures

Outcome measures
Measure	Group 1: Imipenem+Cilastatin/Relebactam n=11 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive imipenem+cilastatin/relebactam IV infusion once every 6 hours and placebo for colistimethate sodium IV infusion once every 12 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 2: Colistimethate Sodium + Imipenem+Cilastatin n=5 Participants Participants with HABP, VABP, cIAI, or cUTI caused by imipenem-nonsusceptible but imipenem/relebactam- and colistin-susceptible pathogens were randomized to receive colistimethate sodium IV infusion once every 12 hours and imipenem+cilastatin IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).	Group 3: Open-Label Imipenem+Cilastatin/Relebactam Participants with HABP, VABP, cIAI, or cUTI caused by imipenem- and colistin-nonsusceptible pathogens received open-label imipenem+cilastatin/relebactam IV infusion once every 6 hours for 5 to 21 days (cIAI and cUTI) or for 7 to 21 days (HABP or VABP).
Percentage of cUTI Participants With FMR at EFU	72.7 Percentage of Participants Interval 42.9 to 90.8	100.0 Percentage of Participants Interval 51.1 to 100.0	—

Adverse Events

Group 1: Imipenem+Cilastatin/Relebactam

Serious events: 4 serious events

Other events: 15 other events

Deaths: 2 deaths

Group 2: Colistimethate Sodium + Imipenem+Cilastatin

Serious events: 5 serious events

Other events: 13 other events

Deaths: 3 deaths

Group 3: Open-Label Imipenem+Cilastatin/Relebactam

Serious events: 3 serious events

Other events: 3 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation.
Publication restrictions are in place

Restriction type: OTHER